Pharmaceutical dosage form bearing pregnancy-friendly indicia

ABSTRACT

A pharmaceutical dosage form comprising at least one active ingredient and destined for administration to pregnant women. The pharmaceutical dosage form bears pregnancy-friendly indicia apt to improve patient compliance with medically recommended dosage regimen resulting in improved product effectiveness. The pregnancy-friendly indicia is also apt to diminish the incidence of erroneous dispensing of or erroneous ingestion of pharmaceutical dosage forms not intended for pregnant women. Also disclosed is a method for achieving improved patient compliance resulting in improved product effectiveness. Also disclosed is a method for diminishing the incidence of erroneous dispensing of or erroneous ingestion of dosage forms not intended for pregnant women. Said methods comprising providing a pharmaceutical dosage form, intended for use by pregnant women, bearing pregnancy-friendly indicia apt to graphically distinguish dosage forms intended to be used during pregnancy from others.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/384,584, filed Mar. 20, 2006, which is a divisional of U.S.application Ser. No. 10/611,803, filed Jul. 1, 2003 (which issued asU.S. Pat. No. 7,560,122), which claims priority to Canadian patentApplication No. CA 2,392,486, filed Jul. 5, 2002. The contents of all ofthe above-referenced applications are incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical dosage forms intendedfor use during pregnancy.

BACKGROUND OF THE INVENTION

During pregnancy a variety of medical conditions require treatment withtherapeutic agents. For instance, in Canada, excessive nausea andvomiting, possibly leading to hyperemesis gravidarum, are routinelytreated with the prescription drug Diclectin® which contains a mixturein equal amounts of two active ingredients, namely pyridoxine HCl anddoxylamine succinate.

Other conditions, pre-existing or developed during pregnancy, forexample: diabetes, hypertension, blood cloths, depressive illness andheart disease are also commonly treated with prescription drugs.

In the case of pre-existing medical conditions numerous studies haveshown that women have a tendency to abruptly stop taking theirmedications upon learning of the pregnancy, due to the perceived fear ofbirth defects¹. In many cases, the risk to the health of the expectantmother and her baby is much higher if she stops or reduces her treatmentthan if she keeps taking the required medications.

Because of this perceived risk of harm to the fetus, otherwise known asthe teratogenic risk, it is common for expectant mothers to discontinuetaking a prescribed drug or to voluntarily diminish the prescribeddosage regimen. This often leads to dosage levels below therapeuticranges in turn leading patients and the medical community to incorrectlyconclude that a particular drug is clinically ineffective.

Discontinuing or altering drug therapy, often against competent medicalprescription, may have grave consequences indeed. The health of theexpectant mother and vicariously of the fetus may be put at great riskbecause of poor compliance with competent medical prescription. In manyinstances, the teratogenic risks must be weighed against the risk ofcatastrophic illness or worsening condition on the part of the expectantmother.

Even discounting the particular problem of patient compliance duringpregnancy, drug therapy patient compliance is a widespread and difficultproblem in the medical community. Non-compliance with prescribed drugdosage regimen is a huge health problem for patients in general. Forexample, it is estimated that less than 25% of outpatients will completea 10 day course of antibiotic therapy for a strep throat or otitismedia.

Matsui² described that non-compliance with prescribed medicationregimens may take many forms, including failure to fill theprescription, incorrect dosage, improper dosing interval, and prematurediscontinuation of the drug. Of course, the problem of non-compliance ismagnified during pregnancy due to the importance of fetal safety.³

Whenever women delay or discontinue use of medications during pregnancydue to fears related to fetal safety, the result may be a worsening ofthe condition and hospitalisation with use of multiple drug therapy.Furthermore, depending of the underlying condition, the worsening of thecondition has serious consequences even including suicidal ideation.Einarson showed in her study¹ on abrupt discontinuation of psychotropicdrugs during pregnancy due to teratogenic fears, that 70.3% of womenreported physical and psychological adverse effects to the point that29.7% reported suicidal ideation (one third of them were hospitalised).

Despite these appalling statistics, the perception of the expectantmother remains shrouded by well-known errors of the past such as thewidely publicized cases of thalidomide-induced fetal malformations. Thegraphic evidence of birth defects attributed to Thalidomide exposureduring early pregnancy has left a teratogenicity stigma on allmedications. Hence, it is commonly thought that all medications are tobe avoided during pregnancy. In the study entitled “Prevention ofUnnecessary Pregnancy Terminations by Counselling Women of Drug,Chemical, and Radiation Exposure During the First Trimester”, (1990)⁴,Koren showed that pregnant women exposed to drugs that are known to benon teratogenic, still perceive that their born-to-be baby has a 24%chance to suffer a major birth defect. This is about the same risk as anintra-uterine exposure to Thalidomide.

Scientific studies aimed at measuring the risk of drugs during pregnancyand patient education and counseling have so far been at the forefrontof efforts to achieve better patient compliance with medicalprescription.

However, even in the case of drugs having an extensively demonstratedrecord of fetal innocuousness, such as Diclectin® used to curb nauseaand vomiting, the perception of latent risk remains. This perception ofrisk is of course carried over from the negative experiences ofthalidomide which was also prescribed for nausea and vomiting duringpregnancy and which was also provided as an oral dosage form. However,in reality, the active ingredient thalidomide and the active ingredientsof Diclectin®, namely pyridoxine HCl and doxylamine succinate arecompletely unrelated. The risk perception carried-over from thalidomideis made apparent from patient compliance inquiries. Patient compliancewith a medically prescribed dosage regimen of Diclectin® is clearlybelow what is recommend in the medical profession.

Even physicians and pharmacists are anxious about their liabilityassociated with prescription or dispensing of medications to pregnantwomen. In the study by Pole⁵, it was shown that even health careprofessionals, after reading four different labels (all of them statingthat drug is safe to be used in pregnancy), have evaluated these labels,as bearing a residual risk. They were unable to fully perceive or acceptthat medication is safe to be used in pregnancy. Patients, physiciansand pharmacists are also worried about erroneous ingestion or dispensingof drugs not intended for use during pregnancy.

Despite the enormous volume of scientific evidence supporting Diclectin®harmlessness to the fetus, pregnant women persistently do not followtheir physician's recommendation as to the adherence to Diclectin®dosage regimen. In most cases, women voluntarily reduce the dosage byhalf. In fact, they do not comply with the proper dosage regimen forDiclectin® to the point that some woman and some physicians believe thatthe medication is not effective. Therefore, non-compliance often resultsin a perception of product effectiveness failure.

Due to non-compliance with medical prescription, patients using lessthan prescribed amounts of Diclectin® will often find themselves insub-therapeutic state. This prevents the medication from being effectiveand may aggravate the mother's condition to the point of developinghyperemesis gravidarum (HG). HG is the most severe end of nausea andvomiting during pregnancy, when a pregnant woman suffers from loss ofmore than 5% of her pre-pregnancy body weight, dehydration, acid-basedisturbances, ketonuria and electrolyte imbalance. At this stage,physicians use intravenous medications that are often not recognised forsafe use during pregnancy in order to control maternal condition. Theuse of these medications poses an unnecessary risk to the fetus. If thislast resort medication appears to be ineffective due to thedeterioration of the woman's condition, a therapeutic abortion may evenbe considered⁶.

In order to diminish potential for birth defects a vitamin intake is nowmedically recommended during pregnancy. For example, clinical evidenceshows that taking folic acid before conception and during the firsttrimester of pregnancy may prevent up to 72% of the congenitalabnormalities spina bifida and anencephaly⁷. Despite this, pregnantwomen are generally non compliant with recommended folic acid intaketreatment thus putting an unborn child at an increased risk of majorbirth defect.

The situation is even worse if pregnant woman has been on a drug therapythat interferes with folic acid receptors (e.g., phenobarbital,phenytoin, carbamazepine, valproic acid). In this case, a pregnant womanis even at greater risk for having a baby with birth defect if she isnot compliant.

Thus there remains an important need for innovative solutions to achievebetter patient compliance of vitamins or drugs recommended for useduring pregnancy.

OBJECTS OF THE INVENTION

An object of the present invention is therefore to provide an improvedoral dosage form for, inter alia, achieving better patient compliancewith vitamins or drugs intended for use during pregnancy.

Another object is to provide a method for improving patient complianceof pregnant women by diminishing their perception of teratogenic riskand by direct implication to improve product effectiveness of dosageforms containing at least one active ingredient and intended for use bypregnant women.

A further object is to provide a method for diminishing the incidence oferroneous ingestion by pregnant women or of erroneous dispensing bypharmacists of therapeutic agents not prescribed to said pregnant women.

SUMMARY OF THE INVENTION

More specifically, in accordance with the present invention, there isprovided a pharmaceutical dosage form comprising at least one activeingredient, such as for example a vitamin supplement or a synergisticcombination of pyridoxine HCl and doxylamine succinate, and destined foradministration to pregnant women, the pharmaceutical dosage form bearingpregnancy-friendly indicia. In a preferred embodiment thepregnancy-friendly indicia is in the shape of a graphical illustrationof a pregnant woman applied to the dosage form itself or to itspackaging. In a most preferred embodiment, the dosage form is destinedfor oral administration.

Also provided is a method of diminishing the perception of teratogenicrisk among pregnant women taking a pharmaceutical dosage form containingat least one active ingredient. The method comprising providing saidpharmaceutical dosage form bearing pregnancy-friendly indicia,preferably in the shape of a graphical illustration of a pregnant womanapplied to the dosage form itself or to its packaging.

Also provided is a method of improving patient compliance of pregnantwomen with medically recommended dosage regimen of at least one activeingredient. The method comprising providing a pharmaceutical dosage formbearing pregnancy-friendly indicia. Improving patient compliance alsoleads to improved product effectiveness because product effectiveness islinked to patient compliance. Thus, the method of the present inventionalso leads to improved product effectiveness.

Also provided is method of diminishing the incidence of erroneousingestion by pregnant women or of erroneous dispensing by pharmacists oftherapeutic agents not prescribed to said pregnant women. The methodcomprising providing a pharmaceutical dosage form comprising at leastone active ingredient prescribed to said pregnant women, the dosage formbearing pregnancy-friendly indicia apt to graphically distinguish dosageforms intended to be used during pregnancy from others.

Other objects, advantages and features of the present invention willbecome more apparent upon reading of the following non-restrictivedescription of preferred embodiments thereof, given by way of exampleonly with reference to the accompanying drawing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a pictorial representation of an improved oral dosage form inaccordance with the present invention and bearing a visible indicia aptto achieve improved patient compliance.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The main object of the present invention is therefore to provide animproved oral dosage form for achieving better patient compliance withdrugs prescribed for use during pregnancy. This objective issurprisingly and effectively achieved by applying pregnancy-friendlyindicia on the dosage form. Dosage form is understood to encompass itspackaging. By “pregnancy-friendly” indicia is meant any graphical ortextual representation apt to be easily recognized as indicative of asafe medication for taking during pregnancy.

In a most preferred embodiment, the pregnancy-friendly indicia are agraphical representation of the profile of a pregnant woman having ahand resting on her stomach region. Such graphical representation isillustrated in FIG. 1 and has a particularly comforting effect onexpectant mothers and have been statistically shown to substantiallylower the perception of teratogenic risk and consequently lead toelevated patient compliance. Such evidence is presented in the examplesprovided below.

Example 1

A study was conducted with 12 pregnant women. This study was aimed attesting if pregnancy-friendly indicia such as the indicia illustrated inFIG. 1 may have a positive impact by reducing the perception ofteratogenic risk of a drug taken during pregnancy, and if it is thecase, which kind of design is most effective in improving patientcompliance.

Different designs of pregnancy-friendly indicia were printed on tablets.This aim was to ascertain if, when used, those indicia would increasethe patients' confidence in taking the tablet during pregnancy byreducing the perception of teratogenic risk. Diminishing the perceptionof teratogenic risk would consequently improve patient compliance and asa result achieve better treatment effectiveness.

The study revealed while all pregnancy-friendly indicia are helpful atdiminishing the perception of teratogenic risk, the most preferredgraphical representation is that of FIG. 1. The graphical representationshown in FIG. 1 would indicate in a clear and precise fashion that themedication has been specifically designed for the pregnant woman.

This surprising positive effect on patient compliance would of coursetranslate itself in the effectiveness of a vitamin or drug treatment anda concurrent reduction of medical complications for the pregnant womanand the fetus.

Example 2

To further validate the findings disclosed in Example 1, anobservational, prospective survey on pregnant women in family practiceoffices and obstetrician offices was conducted. The statistical toolused for measuring the objective of the study (how reassured about fetalsafety woman feels taking one or the other tablet once prescribed tothem) was a validated scientific tool for subjective measurements: avisual analog scale (VAS) from 1-5 (1 being the least safe and 5 beingthe most safe). Patients were told that the prescribed drug, in tabletform, was safe for use in pregnancy and were asked to label on the VAShow reassured about fetal safety they felt when taking the tablet. Theywere shown two different tablets, one plain white and the other whitewith the illustration of FIG. 1 applied to the tablet.

Data was collected from 132 pregnant women and the results are shown inthe table below:

Test: Dual-Sample Assuming Equal Variances

Teratogenic Risk Perception on Scale of 1 to 5 with 1 being GreatestRisk Perception.

Plain Tablet with pregnancy- White friendly indicia tablet as per Figure1 Observations 132 132 Mean Risk 2.5227 3.6969 Perception Variance1.2132 1.3120 P(T <= t) one-tail P < 0.0001

The study clearly showed superiority of the tablet with a printedpregnant woman concerning the perception of the teratogenic risk(results were statistically significant with P<0.0001). The P value of0.0001 signifies that the result of this study as 1/10,000 chance to bethe result of chance only. If we repeat this study 10,000 times, in9,999 cases, the same results would be obtained. Usually P<0.05 isrecognized as medically significant.

Thus, in the sample group of 132 pregnant women, 23.4% felt morereassured about the fetal safety of taking the tablet with a printedpregnant woman as shown in FIG. 1, than a plain white tablet.

Of course, these results would translate themselves directly intoimproved patient compliance by a margin of at least 23.4%. Thus, astrong conclusion emerges that the presence of pregnancy-friendlyindicia on a vitamin or drug to be taken during pregnancy willsignificantly reduce teratogenic risk perception and by the same tokenimprove patient compliance with prescribed dosage regimen.

Although the present invention has been described hereinabove by way ofpreferred embodiments thereof, it can be modified, without departingfrom the spirit and nature of the subject invention as defined in theappended claims. More specifically, the exact appearance ofpregnancy-friendly indicia is variable with the understanding that someindicia will induce greater patient compliance than others. Also, it isto be understood that although examples were given in relation to oraltablets, other pharmaceutical dosages forms are of course covered by thepresent invention. Thus, pregnancy-friendly indicia may appear on theactual dosage form, such as tablet, sugar coated tablet, sublingualtablet, caplet, capsule, gel capsule, chewable tab, pill, suppository,powder, vial, ampoule, pre-filled syringe, nasal spray, pastille, syrup,drops, vaginal ovule, subcutaneous implant, transdermal gel, transdermalpatch, transmucausal strip, pouch, or may also appear on the packagingand labeling of the dosage form.

REFERENCES

-   1. Einarson A., Selby P., Koren G., Abrupt discontinuation of    psychotropic drugs during pregnancy: fear of teratogenic risk and    impact of counseling, J. psychiatry Neurosci 2001; 26(1): 44-48-   2. Matsui D., Drug compliance in pediatrics: Clinical and research    issues. Ped Clin N Amer 1997; 44(1):1-14-   3. Anke M., et al., Questions about drugs: how do pregnant women    solve them? Pharm world Sci 1994 Dec. 2; 16(6):254-9;-   and-   Olesen C., Sondergaard C., Do Pregnant Women Report Use of Dispensed    Medications?, Epidemiology 2001; 12(5):497-501-   4. Koren G., Pastuszak A., Prevention of Unnecessary Pregnancy    Terminations by Counselling Women on Drug, Chemical, and Radiation    Exposure During the First Trimester, Teratology 1990; 41(6):657-61-   5. Pole M., Einarson A., Pairaudeau N.& al., Drug Labeling and Risk    Perceptions of Teratogenicity: A Survey of Pregnant Canadian Women    and Their Health Professionals, J. Clin. Pharmacol. 2000; 40:    573-577-   6. Mazzotta P., Stewart D., Koren G., Magee L A. Factors associated    with elective termination of pregnancy among Canadian and American    women with nausea and vomiting of pregnancy. J. Psychosom Obstet.    Gynecol. 2001; 22(1):7-12-   7. Czeizel A E, Dudas I: Prevention of the first occurance of neural    tube defects by periconceptional vitamin supplementation. N Eng J    Med 1992; 327:1832-1835;-   and-   Pastuszak A., Bhatia D., Okotore B., Koren G., The Effectiveness of    Preconceptional Counseling on Women's Compliance with Folic Acid    Supplementation, Maternal-Fetal Toxicology, A Clinician's Guide,    Third-Edition, 2001:141-149

1. A patient dosage regimen compliance improving pharmaceutical dosageform destined for administration to pregnant women, said pharmaceuticaldosage form containing one or more vitamin supplement or drug, saidpharmaceutical dosage form further comprising a graphical representationof a pregnant woman applied to the outer surface of the dosage form,said graphical representation being visible to the naked eye.
 2. Thepatient dosage regimen compliance improving pharmaceutical dosage formin accordance with claim 1 wherein the dosage form is a tablet.
 3. Thepatient dosage regimen compliance improving pharmaceutical dosage formin accordance with claim 1 wherein said pharmaceutical dosage formcontains a vitamin supplement.
 4. The patient dosage regimen complianceimproving pharmaceutical dosage form in accordance with claim 3 whereinthe dosage form is a tablet.
 5. The patient dosage regimen complianceimproving pharmaceutical dosage form in accordance with claim 3 whereinsaid vitamin supplement comprises folic acid.
 6. The patient dosageregimen compliance improving pharmaceutical dosage form in accordancewith claim 5 wherein the dosage form is a tablet.
 7. The patient dosageregimen compliance improving pharmaceutical dosage form in accordancewith claim 1, wherein the vitamin supplement comprises vitamins orminerals.
 8. The patient dosage regimen compliance improvingpharmaceutical dosage form in accordance with claim 1 wherein saidpharmaceutical dosage form consists of a vitamin supplement.
 9. Thepatient dosage regimen compliance improving pharmaceutical dosage formin accordance with claim 8 wherein the dosage form is a tablet.
 10. Thepatient dosage regimen compliance improving pharmaceutical dosage formin accordance with claim 8 wherein said vitamin supplement comprisesfolic acid.
 11. The patient dosage regimen compliance improvingpharmaceutical dosage form in accordance with claim 10 wherein thedosage form is a tablet.
 12. The patient dosage regimen complianceimproving pharmaceutical dosage form in accordance with claim 1 whereinthe graphical representation being visible to the naked eye is thatshown in FIG.
 1. 13. The patient dosage regimen compliance improvingpharmaceutical dosage form in accordance with claim 12 wherein thedosage form is a tablet.